Pilocarpine, an imidazole alkaloid, is the subject of numerous investigations on account of its varied pharmacological properties. Its outstanding pharmacological activities include diaphoretic effects, stimulation of the parcsympathetic system, miotic actions and, in particular, applications in ophthalmology.
Processes for the preparation of racemic and optically active pilocarpine are known. All these processes are characterized, however, by a comparably large number of synthesis steps, only low overall yields being achieved.
In the synthesis of H. Link and K. Bernauer (Helv. Chem. Acta 55, 1053 (1972)), racemic pilosinine is used as a precursor of pilocarpine. The starting material employed was 5-formyl-1-methylimidazole which is easily accessible from sarcosine in a few steps. The process of Link and Bernauer comprises the Stobbe condensation of an imidazole derivative with succinic acid diester to give a monomaleate whose regioselective reduction leads to butenolide formation, from which pilosinine is produced by catalytic reduction in the last step. The disadvantage of this process is the poor course of the Stobbe condensation, where yields of at most 20% are achieved.
In U.S. Pat. No. 5,180,837, a process for the preparation of racemic pilosinine derivatives from 5-formyl-1-methylimidazole is described. By conversion of the imidazole derivative to a thioacetal, deprotonation thereof and Michael addition to .gamma.-crotonolactone and final desulfurization, the pilosinine derivative is accessible as a pilocarpine precursor. The disadvantage of the process described there is the low overall yield.